4 alpha, 8, 14-trimethyl-18 nor-5 alpha, 8 alpha, 9 beta, 13 alpha, 14 beta androstane-3, 11, 16, 17-tetrone



United States Patent 0 3,347,879 4a,8,14-TRIMEIHYL-18NOR-5a,8oc,9[3,13a,14fi ANDROSTANE-S,11,16,17-TETRONE Imre Bacso,Somerset, and Patrick A. Diassi, Westfield,

N.J., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., NewYork, N.Y., a corporation of Delaware No Drawing. Filed Sept. 9, 1965,Ser. No. 486,213 3 Claims. (Cl. 260-3973) ABSTRACT OF THE DISCLOSUREThis invention relates to the product of 4a,8,-14 trimethyl 18 nor5a,8a,9,9,13u,14;8 androstane 3,11, 16,17-tetrone and intermediatesthereof. The compounds of this invention may be utilized in thetreatment of such conditions as hyperandrogenic acne.

This invention relates to and has as its object the provision of newphysiologically active steroids, processes for their preparation andnovel intermediates useful in said preparation.

More particularly, this invention relates to the production of4a,8,l4-trimethyl 18 nor-5a,8u,9fi,13u,l4,8- androstane3,11,16,17-tetrone and intermediates thereof.

The compound of this invention, in addition to being useful as anintermediate in further chemical synthesis of steroids, has also beenfound to possess certain physiological activity. This compound possessesantiandrogenic activity, i.e., it inhibits the action of androgens andcan be utilized in the treatment of such conditions as hyperandrogenicacne. The compound of this invention may be administered parenterally ororally, the dosage and/ or concentration adjusted for the relativepotency of the particular compound employed.

3,347,879 Patented Oct. 17, 1967 The compound of this invention may beprepared by the processes of this invention beginning with a compoundhaving the formula 0H3. wherein Ac is acyl as the startingzmaterial.

The preferred acyl radicals are those of hydrocarbon carboxylic acids ofless than twelve carbon atoms, as exemplified by the lower alkanoicacids (e.g., acetic, propionic, butyric and tert-pentanoic acid), thelower alkenoic acids, the monocyclic aryl carboxylic acids (e.g.,benozic and toluic acid), the monocyclic aryl lower alkanoic acids(e.g., phenacetic and ,li-phenylpropionic acid), the cycloalkanecarboxylic acids and the cycloalkene carboxylic acids.

5 It has been surprisingly found that when this starting material ishydrolyzed under mild conditions, for example, reacting itwith'perchloric acid and an alcohol such as methanol, ethanol,n-propanol, isopropanol and butanol at room temperature, a mixture of 163 hydroxy-4u,8, 14 trimethyl 18 11,17 trione and a 17 alkoxy -.-4a,8,1'4trimethyl-18- nor 5a,8oz,9fl,l4fi androsta 12,16 diene-S-l l-dione areformed. Oxidation of 16,8 hydroxy 4a,8,14-trimethyl 18 nor5cc,8oc,9,8,130,14,3 androsta-3,1l,17- trione will yield 4oz,8,14trimethyl 18'- 11OI-5a,8oc,913, 13,14/3 androstane 3,11,16,17 tetroneand the tautomeric forms thereof. The reactions 'of thisinvention are asfollows:

III

However, the dione IV may also exist mostly in the tautomeric formsIV(a), IV(b) to W(d) thereof.

The following examples illustrate the invention, but do not limit it.All temperatures are in degrees centigrade unless otherwise stated:

Example 1.-16B hydrxy-4u,8,14-trimethyl-I8-n0r-5a,

811,913,]3a,14,6-andr0sta-3,11,1 7-tri0ne and 17-meth0xy- 4oz,8,14trimethyl 18-n0r-5a,8a,9,8,14 8-androsta-l2, 16-diene-3,11 -dione To asuspension of 1.0 g. of 16;8-acetoxy-4a,8,14-trimethyl 18 nor 5a,8x,95,l3a,14,8 androsta-3,l1,17- trionein 100' ml. of methanol 2.4 ml. ofperchloric acid (70%) are added and the mixture stirred vigorously underhelium for sixteen hours. The resulting solution is carefully dilutedwith water and the crystals which separate are filtered, washed withwater and dried to give 140 mg. of 17 methoxy 40,8,14 trimethyl l8nor-5a, 8a,9fi,l4 8 androsta 12,16-diene-3,l1-dione having a meltingpoint about 175l77 C. [a] --83 (chloroform), A123,, 230 mu (6, 3,100),304 mu (6 10,900), 5.88, 6.13, 0.25 .gg gg 4.10 5., 12-1-1), 4.68 (t..,J=3, 2.5 c.p.s., 16-H), 6.28 (s., OCH3), 8.93 (s., CH3), 8.93 (d., J=6,4-011 Analysis.-Calcd for C H O (342.46): C, 77.15; H, 8.83. Found: C,77.75; H, 8.75.

The combined filtrates are extracted with chloroform which is washedwith water and evaporated under reduced pressure. Crystallization of theresidue from acetone-hexane gives 342 mg. of 16,8 hydroxy 4oz,8,14-trimethyl 18 nor 5a,8a,9fi,130z,14j3 androsta-3,11, 17-trione having amelting point about 2052-07 C.,

Dag-5 (chloroform), Aggy 2.00, 5.73, 5.01 1 33 5;

5.64 (d., J=1O c.p.s., 16aH), 8.71 (5., CH 8.82; (s., CH 8.92, ((1., J=6c.p.s., 4o:CH 8.93 (s,. 3)

Analysis.-Calcd for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.69;H, 8.78.

Example 2.4u,8,14-trimethyl-18-nor-5a8a,9,8,13a,14fi-andr0stane-3,11,16,1 7 -tetr0ne To a solution of 30 mg. of16fl-hydroxy-4a,8,14 trimethyl-18-nor 5u,8a,9p,13a,14pandrosta-3,1l,17-trione in 2.0 ml. of reagent grade acetone 1.0 ml. ofan acetone-water solution (9:1, v.:v.) containing 10 mg. of chromicanhydride and 16 mg. of sulfuric acid per milliliter is added dropwisewith stirring. After five minutes the excess oxidizing agent isdecomposed by adding a few drops of methanol and the mixture is dilutedwith water and extracted with chloroform. The chloroform is washed withwater and evaporated under reduced pressure. Crystallization of theresidue from acetone-hexane gives 17 mg. of 441,8,14 trimethyl 18 nor5a,8m,9fl,13-a,14pandrostane 3,11,16,17 tetr'one having a melting pointabout 228-230 C.,

While there have been described various embodiments of the invention,the compositions and methods described are not intended to be understoodas limiting the scope of the invention, as it is realized that changestherein are possible and it is further intended that each elementrecited in any of the following claims is to be understood as referringto all equivalent elements for accomplishing substantially the sameresults in substantially the same or equivalent manner, it covering theinvention broadly in whatever form its principle may be utilized.

What is claimed is:

1. 411,8, 14 trimethyl 18 nor5a,8a,9fl,1-3a,14-androstane-3,11,16,17-tetrone.

2. 16B hydroxy 442,8,14- trimethyl 18-nor-5a,8a,9fl,13a,14fiandrosta-3,ll,17-trione.

3. A process for the preparation of 16 8-hydroxy-4a8,14- trimethyl l8nOr-5oc,8a,9fl,13a,14 3 androsta-3,l1,l7- trione, which comprisesreacting 16B actoxy 4a,8,14- trimethyl 18-nor 5a,8 a,9fi,13a,14;8androsta-3,11,l7- trione with a mild hydrolyzing agent comprising asolution of an alcohol and perchloric acid.

ELBERT L. ROBERTS, Primary Examiner.

1.4A,8,14-TRIMETHYL-18-NOR-5A,8A,9B,13A,14B-ANDROSTANE-3,11,16,17-TETRONE.